tbuckley/cabot-search huggingface dataset:
The mechanical regulation of RNA binding protein hnRNPC in the failing heart
Authors: Fabiana Martino, Nandan Mysore Varadarajan, Ana Rubina Perestrelo, Vaclav Hejret, Helena Durikova, Dragana Vukic, Vladimir Horvath, Francesca Cavalieri, Frank Caruso, Waleed S. Albihlal, André P. Gerber, Mary A. O’Connell, Stepanka Vanacova, Stefania Pagliari, Giancarlo Forte
Journal: Science Translational Medicine (2022)

Cardiac pathologies are characterized by intense remodeling of the extracellular matrix (ECM) that eventually leads to heart failure. Cardiomyocytes respond to the ensuing biomechanical stress by reexpressing fetal contractile proteins via transcriptional and posttranscriptional processes, such as alternative splicing (AS). Here, we demonstrate that the heterogeneous nuclear ribonucleoprotein C (hnRNPC) is up-regulated and relocates to the sarcomeric Z-disc upon ECM pathological remodeling. We show that this is an active site of localized translation, where the ribonucleoprotein associates with the translation machinery. Alterations in hnRNPC expression, phosphorylation, and localization can be mechanically determined and affect the AS of mRNAs involved in mechanotransduction and cardiovascular diseases, including Hippo pathway effector Yes-associated protein 1. We propose that cardiac ECM remodeling serves as a switch in RNA metabolism by affecting an associated regulatory protein of the spliceosome apparatus. These findings offer new insights on the mechanism of mRNA homeostatic mechanoregulation in pathological conditions.
Adherence to aerobic and muscle-strengthening activities guidelines: a systematic review and meta-analysis of 3.3 million participants across 32 countries
Authors: Antonio Garcia-Hermoso, José Francisco López-Gil, Robinson Ramírez-Vélez, Alicia María Alonso-Martínez, Mikel Izquierdo, Yasmin Ezzatvar
Journal: British Journal of Sports Medicine (2022)

Objective To estimate the global prevalence of meeting the WHO guidelines for both aerobic and muscle-strengthening activities (MSA) in populations aged ≥5 years, and whenever possible to explore this prevalence according to sociodemographic and lifestyle factors. Design A systematic review and meta-analysis. Data sources Five databases were systematically searched for studies published from inception to September 2022. Eligibility criteria for selecting studies Articles with representative samples aged ≥5 years reporting the prevalence of meeting both aerobic and MSA guidelines were included. Results Twenty-one studies comprising 3 390 001 individuals from 32 countries were included. Overall adherence to the aerobic and MSA guidelines was 17.12% (95% CI 15.42% to 18.88%) in adults ≥18 years (n=3 346 723). Among adolescents aged 12–17 years, adherence to both guidelines was 19.74% (95% CI 14.72% to 25.31%) (n=43 278). No studies reported data for children aged 5–11 years. Women, older age, low/medium education levels, underweight or obesity, and poor and moderate self-rated health were associated with lower adherence to the physical activity guidelines (p&lt;0.001) among adults, although the prevalence remained very low in all cases. Subgroup analyses were not conducted with children and adolescents due to a lack of studies. Conclusions Only one out of five adolescents and adults met the recommended combined aerobic and MSA guidelines. Large-scale public health interventions promoting both types of exercise are needed to reduce the associated burden of non-communicable diseases. PROSPERO registration number CRD42022338422.
Simultaneous analysis of mutations and methylations in circulating cell-free DNA for hepatocellular carcinoma detection
Authors: Pei Wang, Qianqian Song, Jie Ren, Weilong Zhang, Yuting Wang, Lin Zhou, Dongmei Wang, Kun Chen, Liping Jiang, Bochao Zhang, Wanqing Chen, Chunfeng Qu, Hong Zhao, Yuchen Jiao
Journal: Science Translational Medicine (2022)

Cell-free DNA (cfDNA)–based liquid biopsy is a promising approach for the early detection of cancer. A major hurdle is the limited yield of cfDNA from one blood draw, limiting the use of most samples to one test of either mutation or methylation. Here, we develop a technology, Mutation Capsule Plus (MCP), which enables multiplex profiling of one cfDNA sample, including simultaneous detection of genetic and epigenetic alterations and genome-wide discovery of methylation markers. With this technology, we performed de novo screening of methylation markers on cfDNA samples from 30 hepatocellular carcinoma (HCC) cases and 30 non-HCC controls. The methylation markers enriched in HCC cfDNA were further profiled in parallel with a panel of mutations on a training cohort of 60 HCC and 60 non-HCC cases, resulting in an HCC detection model. We validated the model in an independent retrospective cohort with 58 HCC and 198 non-HCC cases and got 90% sensitivity with 94% specificity. Furthermore, we applied the model to a prospective cohort of 311 asymptomatic hepatitis B virus carriers with normal liver ultrasonography and serum AFP concentration. The model detected four of the five HCC cases in the cohort, showing 80% sensitivity and 94% specificity. These findings demonstrate that the MCP technology has potential for the discovery and validation of multiomics biomarkers for the noninvasive detection of cancer. This study also provides a comprehensive database of genetic and epigenetic alterations in the cfDNA of a large cohort of HCC cases and high-risk non-HCC individuals.
Allogeneic natural killer cell therapy
Authors: Melissa M. Berrien-Elliott, Miriam T. Jacobs, Todd A. Fehniger
Journal: Blood (2022)

Abstract Interest in adoptive cell therapy for treating cancer is exploding owing to early clinical successes of autologous chimeric antigen receptor (CAR) T lymphocyte therapy. However, limitations using T cells and autologous cell products are apparent as they (1) take weeks to generate, (2) utilize a 1:1 donor-to-patient model, (3) are expensive, and (4) are prone to heterogeneity and manufacturing failures. CAR T cells are also associated with significant toxicities, including cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and prolonged cytopenias. To overcome these issues, natural killer (NK) cells are being explored as an alternative cell source for allogeneic cell therapies. NK cells have an inherent ability to recognize cancers, mediate immune functions of killing and communication, and do not induce graft-versus-host disease, cytokine release syndrome, or immune effector cell–associated neurotoxicity syndrome. NK cells can be obtained from blood or cord blood or be derived from hematopoietic stem and progenitor cells or induced pluripotent stem cells, and can be expanded and cryopreserved for off-the-shelf availability. The first wave of point-of-care NK cell therapies led to the current allogeneic NK cell products being investigated in clinical trials with promising preliminary results. Basic advances in NK cell biology and cellular engineering have led to new translational strategies to block inhibition, enhance and broaden target cell recognition, optimize functional persistence, and provide stealth from patients’ immunity. This review details NK cell biology, as well as NK cell product manufacturing, engineering, and combination therapies explored in the clinic leading to the next generation of potent, off-the-shelf cellular therapies for blood cancers.
Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti–PD-1 immunotherapy
Authors: Balamayooran Theivanthiran, Nagendra Yarla, Tarek Haykal, Y.-Van Nguyen, Linda Cao, Michelle Ferreira, Alisha Holtzhausen, Rami Al-Rohil, April K.S. Salama, Georgia M. Beasley, Michael P. Plebanek, Nicholas C. DeVito, Brent A. Hanks
Journal: Science Translational Medicine (2022)

The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome–heat shock protein 70 (HSP70) signaling axis is triggered by CD8 + T cell cytotoxicity and contributes to the development of adaptive resistance to anti–programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti–PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti–PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti–PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti–PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.
Precise genomic editing of pathogenic mutations in <i>RBM20</i> rescues dilated cardiomyopathy
Authors: Takahiko Nishiyama, Yu Zhang, Miao Cui, Hui Li, Efrain Sanchez-Ortiz, John R. McAnally, Wei Tan, Jiwoong Kim, Kenian Chen, Lin Xu, Rhonda Bassel-Duby, Eric N. Olson
Journal: Science Translational Medicine (2022)

Mutations in RNA binding motif protein 20 ( RBM20 ) are a common cause of familial dilated cardiomyopathy (DCM). Many RBM20 mutations cluster within an arginine/serine-rich (RS-rich) domain, which mediates nuclear localization. These mutations induce RBM20 mis-localization to form aberrant ribonucleoprotein (RNP) granules in the cytoplasm of cardiomyocytes and abnormal alternative splicing of cardiac genes, contributing to DCM. We used adenine base editing (ABE) and prime editing (PE) to correct pathogenic p.R634Q and p.R636S mutations in the RS-rich domain in human isogenic induced pluripotent stem cell (iPSC)–derived cardiomyocytes. Using ABE to correct RBM20 R634Q human iPSCs, we achieved 92% efficiency of A-to-G editing, which normalized alternative splicing of cardiac genes, restored nuclear localization of RBM20, and eliminated RNP granule formation. In addition, we developed a PE strategy to correct the RBM20 R636S mutation in iPSCs and observed A-to-C editing at 40% efficiency. To evaluate the potential of ABE for DCM treatment, we also created Rbm20 R636Q mutant mice. Homozygous (R636Q/R636Q) mice developed severe cardiac dysfunction, heart failure, and premature death. Systemic delivery of ABE components containing ABEmax-VRQR-SpCas9 and single-guide RNA by adeno-associated virus serotype 9 in these mice restored cardiac function as assessed by echocardiography and extended life span. As seen by RNA sequencing analysis, ABE correction rescued the cardiac transcriptional profile of treated R636Q/R636Q mice, compared to the abnormal gene expression seen in untreated mice. These findings demonstrate the potential of precise correction of genetic mutations as a promising therapeutic approach for DCM.
Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop
Authors: Yichao Hua, Gerlanda Vella, Florian Rambow, Elizabeth Allen, Asier Antoranz Martinez, Marie Duhamel, Akira Takeda, Sirpa Jalkanen, Steffie Junius, Ann Smeets, David Nittner, Stefanie Dimmeler, Thomas Hehlgans, Adrian Liston, Francesca Maria Bosisio, Giuseppe Floris, Damya Laoui, Maija Hollmén, Diether Lambrechts, Pascal Merchiers, Jean-Christophe Marine, Susan Schlenner, Gabriele Bergers
Journal: Cancer Cell (2022)

The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 T cell progenitors that differentiate into GrzB+PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.
Predicting butyrate- and propionate-forming bacteria of gut microbiota from sequencing data
Authors: Berenike Kircher, Sabrina Woltemate, Frank Gutzki, Dirk Schlüter, Robert Geffers, Heike Bähre, Marius Vital
Journal: Gut Microbes (2022)

The bacteria-derived short-chain fatty acids (SCFAs) butyrate and propionate play important (distinct) roles in health and disease, and understanding the ecology of respective bacteria on a community-wide level is a top priority in microbiome research. Applying sequence data (metagenomics and 16S rRNA gene) to predict SCFAs production in vitro and in vivo, a clear split between butyrate- and propionate-forming bacteria was detected with only very few taxa exhibiting pathways for the production of both SCFAs. After in vitro growth of fecal communities from distinct donors (n = 8) on different substrates (n = 7), abundances of bacteria exhibiting pathways correlated with respective SCFA concentrations, in particular in the case of butyrate. For propionate, correlations were weaker, indicating that its production is less imprinted into the core metabolism compared with butyrate-forming bacteria. Longitudinal measurements in vivo (n = 5 time-points from 20 subjects) also revealed a correlation between abundances of pathway-carrying bacteria and concentrations of the two SCFAs. Additionally, lower bacterial cell concentrations, together with higher stool moisture, promoted overall bacterial activity (measured by flow cytometry and coverage patterns of metagenome-assembled genomes) that led to elevated SCFA concentrations with over-proportional levels of butyrate. Predictions on pathway abundances based on 16S rRNA gene data using our in-house database worked well, yielding similar results as metagenomic-based analyses. Our study indicates that stimulating growth of butyrate- and propionate-producing bacteria directly leads to more production of those compounds, which is governed by two functionally distinct bacterial groups facilitating the development of precision intervention strategies targeting either metabolite.
Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer
Authors: Ruoyan Li, John R. Ferdinand, Kevin W. Loudon, Georgina S. Bowyer, Sean Laidlaw, Francesc Muyas, Lira Mamanova, Joana B. Neves, Liam Bolt, Eirini S. Fasouli, Andrew R.J. Lawson, Matthew D. Young, Yvette Hooks, Thomas R.W. Oliver, Timothy M. Butler, James N. Armitage, Tev Aho, Antony C.P. Riddick, Vincent Gnanapragasam, Sarah J. Welsh, Kerstin B. Meyer, Anne Y. Warren, Maxine G.B. Tran, Grant D. Stewart, Isidro Cortés-Ciriano, Sam Behjati, Menna R. Clatworthy, Peter J. Campbell, Sarah A. Teichmann, Thomas J. Mitchell
Journal: Cancer Cell (2022)

Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood. We find that the tissue-type location of CD8+ T cell clonotypes largely defines their exhaustion state with intra-tumoral spatial heterogeneity that is not well explained by somatic heterogeneity. De novo mutation calling from single-cell RNA-sequencing data allows us to broadly infer the clonality of stromal cells and lineage-trace myeloid cell development. We report six conserved meta-programs that distinguish tumor cell function, and find an epithelial-mesenchymal transition meta-program highly enriched at the tumor-normal interface that co-localizes with IL1B-expressing macrophages, offering a potential therapeutic target.
Prognostic Relevance of Dominant Blood T-Cell Clones in Early Mycosis Fungoides—Reply
Authors: Yann Charli-Joseph, Laura Beth Pincus, Weiyun Z. Ai
Journal: JAMA Dermatology (2022)

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Risk Factors Associated With First and Second Primary Melanomas in a High-Incidence Population
Authors: Catherine M. Olsen, Nirmala Pandeya, Jean Claude Dusingize, Rachel E. Neale, Stuart MacGregor, Matthew H. Law, David C. Whiteman, Nicholas K. Hayward, Kiarash Khosrotehrani, Louisa G. Gordon
Journal: JAMA Dermatology (2022)

An increasing number of people develop more than 1 primary melanoma, yet to date, no population-based prospective cohort studies have reported on risk factors for developing first vs second primary melanomas.To compare the clinical characteristics of first and second melanomas and then to estimate the relative risks of developing 1 vs multiple melanomas associated with demographic, phenotypic, sun exposure, and genetic factors.This population-based prospective cohort study included men and women aged 40 to 69 years recruited in 2011 and followed up until December 2018 in Queensland, Australia. Data analysis was performed from February to July 2022.Self-reported information about demographic, phenotypic, and sun exposure measures captured using a survey completed at baseline, and polygenic risk score for melanoma.Incident first or second primary melanoma diagnosis, and histologic and clinical characteristics thereof. The Wei-Lin-Weissfeld model for recurrent events was used to estimate the association of each factor with the risks of first and second primary melanoma.A total of 38 845 patients (mean [SD] age at baseline, 56.1 [8.2] years; 17 775 men and 21 070 women) were included in the study. During a median follow-up period of 7.4 years, 1212 (3.1%) participants had a single primary melanoma diagnosis, and 245 (0.6%) had a second primary melanoma diagnosis. Second melanomas were more likely than first melanomas to be in situ; for invasive tumors, second melanomas were more likely to be thin (ie, ≤1 mm) than first melanomas. Having many moles at age 21 years (self-reported using visual scoring tool) was more strongly associated with second (hazard ratio [HR], 6.36; 95% CI, 3.77-10.75) than first primary melanoma (HR, 3.46; 95% CI, 2.72-4.40) (P value for difference between the HRs = .01). A high genetic predisposition (ie, polygenic risk score in tertile 3) was also more strongly associated with second (HR, 3.28; 95% CI, 2.06-5.23) than first melanoma (HR, 2.06; 95% CI, 1.71-2.49; P = .03). Second melanomas were more strongly associated with a history of multiple skin cancer excisions (HR, 2.63; 95% CI, 1.80-3.83) than first melanomas (HR, 1.86; 95% CI, 1.61-2.16; P = .05). For all other phenotypic characteristics and sun exposure measures, similarly elevated associations with first vs second melanomas were observed.Findings of this cohort study suggest that within the general population, the presence of many nevi and having a high genetic predisposition to melanoma were associated with the highest risks of developing second primary melanomas.
Association of Opioid and Stimulant Use Disorder Diagnoses With Fatal and Nonfatal Overdose Among People With a History of Incarceration
Authors: Heather Palis, Wenqi Gan, Chloe Xavier, Roshni Desai, Marnie Scow, Kali-olt Sedgemore, Leigh Greiner, Tonia Nicholls, Amanda Slaunwhite
Journal: JAMA Network Open (2022)

Importance Studies have suggested a rise in opioid- and stimulant-involved overdoses in recent years in North America. This risk may be acute for individuals who have had contact with the criminal justice system, who are particularly vulnerable to overdose risk. Objective To examine the association of opioid and/or stimulant use disorder diagnoses with overdose (fatal and nonfatal) among people with histories of incarceration. Design, Setting, and Participants In this cohort study, population-based health and corrections data were retrieved from the British Columbia Provincial Overdose Cohort, which contains a 20% random sample of residents of British Columbia. The analysis included all people in the 20% random sample who had a history of incarceration between January 1, 2010, and December 31, 2014. Outcomes were derived from 5-years of follow-up data (January 1, 2015, to December 31, 2019). Statistical analysis took place from January 2022 to June 2022. Exposures Substance use disorder diagnosis type (ie, opioid use disorder, stimulant use disorder, both, or neither), sociodemographic, health, and incarceration characteristics. Main Outcomes and Measures Hazard ratios (HRs) are reported from an Andersen-Gill model for recurrent nonfatal overdose events and from a Fine and Gray competing risk model for fatal overdose events. Results The study identified 6816 people (5980 male [87.7%]; 2820 aged &amp;amp;lt;30 years [41.4%]) with histories of incarceration. Of these, 293 (4.3%) had opioid use disorder only, 395 (6.8%) had stimulant use disorder only, and 281 (4.1%) had both diagnoses. During follow-up, 1655 people experienced 4026 overdoses including 3781 (93.9%) nonfatal overdoses, and 245 (6.1%) fatal overdoses. In adjusted analyses, the hazard of both fatal (HR, 2.39; 95% CI, 1.48-3.86) and nonfatal (HR, 2.45; 95% CI, 1.94-3.11) overdose was highest in the group with both opioid and stimulant use disorder diagnoses. Conclusions and Relevance This cohort study of people with a history of incarceration found an elevated hazard of fatal and nonfatal overdose among people with both opioid and stimulant use disorder diagnoses. This study suggests an urgent need to address the service needs of individuals who have had contact with the criminal justice system and who co-use opioids and stimulants.